This application is a 371 of PCT/EP99/03064 filed May 5, 1999.
The present invention relates to thienyl substituted acylguanidine derivatives, such as compounds of the formula I 
in which R1, R2, R4, R6, A, B and D have the meanings indicated below, their physiologically tolerable salts and their prodrugs. The compounds of the present invention are valuable pharmaceutical active compounds. They are vitronectin receptor antagonists and inhibitors of bone resorption by osteoclasts. They are suitable, for example, for the therapy and prophylaxis of diseases which are caused at least partially by an undesired extent of bone resorption, for example of osteoporosis. The invention furthermore relates to processes for the preparation of thienyl substituted acylguanidines, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
Human bones are subject to a constant dynamic renovation process comprising bone resorption and bone formation. These processes are controlled by types of cell specialized for these purposes. Bone resorption is based on the destruction of bone matriy by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption. Osteoporosis is a disease characterized by low bone mass and enhanced bone fragility resulting in an increased risk of fractures. It results from a deficit in new bone formation versus bone resorption during the ongoing remodelling process. Conventional osteoporosis treatment includes, for example, the administration of bisphosphonates, estrogens, estrogen/progesterone (hormone replacement therapy or HRT), estrogen agonists/antagonists (selective estrogen receptor modulators or SERMs), calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride (Jardine et al., Annual Reports in Medicinal Chemistry 1996, 31, 211).
Activated osteoclasts are polynuclear cells having a diameter of up to 400 xcexcm which remove bone matrix. Activated osteoclasts become attached to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called xe2x80x9csealing zonexe2x80x9d, the region between their cell membrane and the bone matrix. The acidic environment and the proteases cause the destruction of the bone. The compounds of the present invention inhibit bone resorption by osteoclasts.
Studies have shown that the attachment of osteoclasts to the bones is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors which include, inter alia, the fibrinogen receptor xcex1IIbxcex23 on blood platelets and the vitronectin receptor xcex1vxcex23. The vitronectin receptor xcex1vxcex23 is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the vascular smooth musculature, osteoclasts and tumor cells. The vitronectin receptor xcex1vxcex23, which is expressed on the osteoclast membrane controls the process of osteoclast attachment to the bones and bone resorption, and thus contributes to osteoporosis. xcex1vxcex23 in this case binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospondin which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor antibody (23C6) which inhibit tooth destruction by osteoclasts and the migration of osteoclasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. describe echistatin, an RGD containing peptide from snake venom, as a potent inhibitor of bone resorption in a tissue culture and as an inhibitor of osteoclast adhesion to the bones. Fisher et al. (Endocrinology 1993, 132, 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo. Yamamoto et al. (Endocrinology 1998, 139, 1411) show that echistatin prevents bone loss in ovarectomized mice and rats.
It was furthermore shown that the vitronectin xcex1vxcex23 on human cells of the vascular smooth musculature of the aorta stimulates the migration of these cells into the neointima, which finally leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815). Yue et al. (Pharmacology Reviews and Communications 1998, 10, 9) show the inhibition of neointima formation using an xcex1vxcex23 antagonist.
Brooks et al. (Cell 1994, 79, 1157) showed that antibodies against xcex1vxcex23 or xcex1vxcex23 antagonists can cause a shrinkage of tumors by inducing the apoptosis of blood vessel cells during angiogenesis. The vitronectin receptor xcex1vxcex23 is also involved in the progression of a variety of other types of cancer, and is overexpressed in malignant melanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry 1996, 31, 191). The melanoma invasiveness correlated with this overexpression (Stracke et al., Encylopedia of Cancer, volume III, 1855, Academic Press, 1997; Hillis et al., Clinical Science 1996, 91, 639). Carron et al. (Cancer Res. 1998, 58, 1930) describe the inhibition of tumor growth and the inhibition of hypercalcemia of malignancy using an xcex1vxcex23 antagonist.
Friedlander et al. (Science 1995, 270, 1500) describe anti-xcex1vxcex23 antibodies or xcex1vxcex23 antagonists which inhibit the bFGF-induced angiogenesis processes in the rat eye, a property which can be used therapeutically in the treatment of retinopathies. Storgard et al. (J. Clin. Invest 1999, 103, 47) describe the use of xcex1vxcex23 antagonists in the treatment of arthritic diseases. Hammes et al. showed that cyclic peptidic xcex1vxcex23 antagonists inhibit angiogenesis in an ischemic model of retinopathy (Nature Medicine 1996, 2, 529). Influencing of the vitronectin receptor or of the interactions in which it is involved thus offers the possibility of influencing different disease states for whose therapy and prophylaxis there continues to be a need for suitable pharmaceutical active ingredients.
Patent application WO-A-94/12181 describes substituted aromatic or nonaromatic ring systems, and WO-A-94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528586 and EP-A-528587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives, and WO-A-95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO-A-96/00574 describes benzodiazepines, and WO-A-96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a nitrogen-bearing 5-membered ring, as vitronectin receptor antagonists. EP-A-820991 discloses cycloalkyl derivatives, international patent application PCT/EP98/08051 discloses carbamic ester derivatives and international patent application PCT/EP99/00242 discloses sulfonamides which are vitronectin receptor antagonists. Certain thiophene derivatives which are potent and selectively acting fibrinogen receptor antagonists are disclosed in WO-A-94/08577. Further investigations have shown that the thienyl substituted acylguanidines of the present invention are particularly strong inhibitors of the vitronectin receptor and of bone resorption by osteoclasts.
Thus, a subject of the present invention are compounds of the formula I, 
in which
A is a saturated or unsaturated bivalent (C1-C9)-alkylene residue or a bivalent (C3-C7)-cycloalkylene residue, wherein the alkylene residue and the cycloalkylene residue each is unsubstituted or is substituted by one or more residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo;
B is hydrogen, xe2x80x94NHxe2x80x94COxe2x80x94OR5, xe2x80x94NHxe2x80x94SO2xe2x80x94R5, xe2x80x94NHxe2x80x94SO2xe2x80x94(C6-C14)-aryl, xe2x80x94NHxe2x80x94SO2xe2x80x94(C5-C14)-heteroaryl, xe2x80x94NHxe2x80x94COxe2x80x94R5, xe2x80x94NHxe2x80x94COxe2x80x94(C6-C14)-aryl, xe2x80x94NHxe2x80x94COxe2x80x94(C5-C14)-heteroaryl, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R5, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(C6-C14)-aryl, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(C5-C14)-heteroaryl, xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94R5, xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94(C6-C14)-aryl or xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94(C5-C14)-heteroaryl;
D is hydrogen, (C6-C14)-aryl, (C5-C14)-heteroaryl or R5;
R1 and R2 independently of one another are hydrogen or (C1-C6)-alkyl which is unsubstituted or substituted by one or more residues R3,
or R1 and R2 together are a saturated or unsaturated bivalent (C2-C6)-alkylene residue which is unsubstituted or is substituted by one or more residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5- to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by one or more residues R3 and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbonxe2x80x94carbon bond in the (C2-C9)-alkylene residue;
R3 is (C1-C8)-alkyl, (C5-C14)-alkoxy, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C4)-alkyl-, halogen, trifluoromethyl, hydroxyl, nitro or amino;
R4 is hydrogen, (C1-C6)-alkyl-COxe2x80x94Oxe2x80x94(C1-C4)-alkyl- or (C1-C6)-alkyl which is unsubstituted or is substituted by a residue from the series consisting of hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94, xe2x80x94NR7R7a and xe2x80x94N+R7R7aR7b Qxe2x88x92, where R7, R7a and R7b independently of one another are hydrogen, (C1-C6)-alkyl, (C5-C14)-aryl or (C5-C14)-aryl-(C1-C5)-alkyl- and Qxe2x88x92 is a physiologically tolerable anion, or R4 is one of the residues 
xe2x80x83in which the bonds via which the residues are bonded, are indicated by dashed lines;
R5 is (C1-C14)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl-, (C6-C14)-aryl-(C1-C6)-alkyl- or (C5-C14)-heteroaryl-(C1-C6)-alkyl-, where the (C1-C14)-alkyl residue is unsubstituted or substituted by one or more halogen atoms and where the aryl residue and the heteroaryl residue is unsubstituted or is substituted by one or more residues R3;
R6 is hydrogen, (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94, hydroxyl, (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94Oxe2x80x94 or nitro; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
In addition to the compounds of the formula I in which the two residues bonded to the central thiophene ring are bonded to the 2-position and the 5-position of the thiophene ring, a further subject of the present invention are the positional isomers of the compounds of the formula I with a different substitution pattern on the central thiophene ring. For example, a subject of the present invention are compounds in which one of the two residues bonded to the central thiophene ring in the formula I is bonded to the 2-position of the thiophene ring and the other is bonded to the 4-position of the thiophene ring, including the isomer in which the residue R4Oxe2x80x94COxe2x80x94CHBxe2x80x94CHDxe2x80x94NHxe2x80x94COxe2x80x94 is bonded to the 2-position and the residue R6R2Nxe2x80x94C(xe2x95x90NR1)xe2x80x94NHxe2x80x94COxe2x80x94Axe2x80x94 is bonded to the 4-position, as well as the isomer in which the residue R6R2Nxe2x80x94C(xe2x95x90NR1)xe2x80x94NHxe2x80x94COxe2x80x94Axe2x80x94 is bonded to the 2-position and the residue R4xe2x80x94COxe2x80x94CHBxe2x80x94CHDxe2x80x94NHxe2x80x94COxe2x80x94 is bonded to the 4-position. Further, a subject of the present invention are, for example, compounds in which one of the two residues bonded to the central thiophene ring in the formula I is bonded to the 3-position of the thiophene ring and the other is bonded to the 4-position of the thiophene ring. In addition, compounds of the formula I and positional isomers thereof in which the central thiophene ring carries one or two further substituents, for example identical or different (C1-C4)-alkyl groups and/or halogen atoms, form a part of the present invention. All statements above and below relating to the compounds of the formula I also apply to such positional isomers of the compounds of the formula I and to such analogues substituted on the thiophene ring which form a part of the present invention. Whenever in the following statements are made with respect to the compounds of the formula I, such positional isomers with a different substitution pattern and such substituted analogues have expressly to be understood as being included.
All residues which can occur several times in the compounds of the formula I, for example substituents present in groups like alkyl groups, alkylene groups, aryl groups, etc., or residues like R3, R5 etc., can each independently of one another have the meanings indicated. All such residues can each be different or identical.
Alkyl residues can be straight-chain or branched, saturated or mono- or polyunsaturated. This also applies if they carry substituents or occur as substituents of other residues, for example in alkoxy residues, alkoxycarbonyl residues or arylalkyl residues. The same applies to alkylene residues. Examples of suitable alkyl residues are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, hexadecyl, octadecyl, including the n-isomers of all these alkyl residues as well as, for example, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The bivalent residues corresponding to the abovementioned monovalent residues, for example methylene, ethylene, 1,3-propylene, 1,2-propylene (=methylethylene), 2,3-butylene (=1,2-dimethylethylene), 1,4-butylene, 1,6-hexylene, are examples of alkylene residues (=alkanediyl residues).
Unsaturated alkyl residues are, for example, alkenyl residues such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl, or alkynyl residues such as ethynyl, 1-propynyl or propargyl. Unsaturated alkylene residues such as alkenylene residues (=alkenediyl residues) and alkynylene residues (=alkynediyl residues) can likewise be straight-chain or branched. Examples of alkenylene residues are vinylene, propenylene or 2-butenylene, examples of alkynylene residues are ethynylene or propynylene.
Cycloalkyl residues can be monocyclic, bicyclic, tricyclic, tetracyclic or pentacyclic, provided that they contain a suitable number of carbon atoms and the parent polycyclic hydrocarbon system is stable. Monocycloalkyl residues are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl, which can be unsubstituted but can also be substituted by one or more identical or different residues, for example by (C1-C4)-alkyl residues like methyl. Examples of substituted monocycloalkyl residues which may be mentioned are 4-methylcyclohexyl or 2,3-dimethylcyclopentyl. The bivalent residues corresponding to the abovementioned monovalent residues, for example 1,2-cyclopropylene, 1,2-cyclobutylene, 1,2-cyclopentylene, 1,2-cyclohexylene, 1,2-cycloheptylene, 1,3-cyclohexylene, 1,4-cycohexylene, etc. are examples of cycloalkylene residues (=cycloalkanediyl residues).
Bicycloalkyl residues, tricycloalkyl residues, tetracycloalkyl residues and pentacycloalkyl residues preferably are (C6-C12)-cycloalkyl residues. Like monocyclic cycloalkyl residues, polycyclic cycloalkyl residues can be unsubstituted or substituted in any desired suitable positions, for example by one or more oxo groups and/or one or more identical or different halogen atoms and/or one or more identical or different (C1-C4)-alkyl groups, for example methyl or isopropyl groups, preferably methyl groups. The free bond of a polycyclic cycloalkyl residue via which it is bonded can be located in any desired position in the molecule; the residue can thus be bonded via a bridgehead atom or via an atom in a bridge. The free bond can also be located in any desired stereochemical position, for example in an exo-position or an endo-position. Examples of bicycloalkyl residues and tricycloalkyl residues are, camphanyl, bornyl, adamantyl, such as 1-adamantyl and 2-adamantyl, caranyl, epiisobornyl, epibomyl, norbornyl and norpinanyl. An example of a pentacycloalkyl residue is the cubyl residue (pentacyclo[4.2.0.02.5.03.8.04.7]octyl residue).
Examples of halogen are fluorine, chlorine, bromine or iodine.
If not stated otherwise, (C5-C14)-aryl includes heterocyclic (C5-C14)-aryl residues (xe2x95x90(C5-C14)-heteroaryl residues) in which one or more of the 5 to 14 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur, and carbocyclic (C6-C14)-aryl residues. Examples of carbocyclic (C6-C14)-aryl residues, and thus also examples of (C5-C14)-aryl residues, are phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, where 1-naphthyl, 2-naphthyl and in particular phenyl are preferred. If not stated otherwise aryl residues, for example phenyl residues, can be unsubstituted or substituted by one or more residues, for example by one, two, three, four or five identical or different residues, preferably by one, two or three residues. In particular, if not stated otherwise, aryl residues can be substituted by identical or different residues from the series consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, ethylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy. Generally, only up to two nitro groups can occur as substituents in the compounds of the formula I according to the invention.
In monosubstituted phenyl residues, the substituent can be located in the 2-position, the 3-position or the 4-position, the 3- and the 4-position being preferred. If phenyl is disubstituted the substituents can be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl residues, the substituents can be in the 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position.
Beside carbocyclic systems, (C5-C14)-aryl residues can also be monocyclic or polycyclic aromatic ring systems in which 1, 2, 3, 4 or 5 ring carbon atoms of the corresponding cyclic hydrocarbon system are replaced by heteroatoms, provided that the resulting aromatic heterocyclic system is stable. Thus, in such heterocyclic (C5-C14)-aryl residues 5 to 14 ring atoms are present of which 1 to 5 ring atoms are heteroatoms and the others are carbon atoms. The heteroatoms can be identical or different. In particular the heteroatoms are selected from the series consisting of nitrogen, oxygen and sulfur. Examples of such heterocyclic (C5-C14)-aryl residues (xe2x95x90(C5-C14)-heteroaryl residues), and thus also examples of (C5-C14)-aryl residues, are pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl such as 2-pyridyl or 3-pyridyl or 4-pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, xcex2-carbolinyl, or benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivatives of these residues. If not stated otherwise, the above statements relating to substituents on carbocylic aryl residues also apply to heteroaryl residues. Thus, heteroaryl residues can be unsubstituted or substituted in all desired positions by one or more substituents, for example one, two, three, four or five identical or different substituents, in particular those substituents which are listed above as substituents on carbocyclic aryl systems.
In the series of heteroaryl residues, monocyclic or bicyclic aromatic ring systems are preferred which contain 1, 2 or 3 identical or different ring heteroatoms, in particular 1 or 2 ring heteroatoms, from the series consisting of N, O and S, and which are unsubstituted or substituted by 1, 2 or 3 identical or different substituents from the series consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl. Particularly preferred heteroaryl residues are monocyclic or bicyclic aromatic 5- to 10-membered ring systems which contain 1 to 3 heteroatoms, in particular 1 or 2 heteroatoms, from the series consisting of N, O and S and which are unsubstituted or substituted by 1 to 2 identical or different substituents from the series consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyl and benzyloxy.
Optically active carbon atoms present in the compounds of the formula I can independently of one another have R configuration or S configuration. The compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers, for example in the form of racemates, or in the form of mixtures of diastereomers. The present invention relates to pure enantiomers and mixtures of enantiomers as well as to pure diastereomers and mixtures of diastereomers. The invention comprises mixtures of two or of more than two stereoisomers of the formula I, and it comprises all ratios of stereoisomers in the mixtures. With respect to ring systems like cycloalkyl residues or cycloalkylene residues, in which the relative position of substituents or free bonds, for example the relative position of the two free bonds in cycloalkylene residues, is usually designated as trans position or cis position, respectively, the present invention comprises the cis isomers as well as the trans isomers, and also mixtures of cis isomers and trans isomers in all ratios. Double bonds in the compounds of the formula I can independently have E configuration or Z configuration. With respect to each occurrence of E/Z isomerism, the present invention comprises both pure E isomers and pure Z isomers and E/Z mixtures in all ratios. The invention also comprises all tautomeric forms of the compounds of the formula I, for example beside the form shown in the formula I also the form in which the acylguanidine unit is present as a xe2x80x94COxe2x80x94Nxe2x95x90C(NHR1)xe2x80x94NR2R6 group and all other forms which differ from one another by different positions of mobile hydrogen atoms. If desired, individual stereoisomers can be obtained from mixtures of stereoisomers by customary separation techniques well known to one skilled in the art, or they can be obtained by using stereochemical uniform starting materials or employing stereoselective syntheses. Diastereomers including cis/trans isomers and E/Z isomers can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary resolution methods like, for example, chromatography on chiral phases or crystallization of derivatives.
Physiologically tolerable salts of the compounds of formula I are, in particular, nontoxic, physiologically utilizable salts or pharmaceutically utilizable salts. Such salts of compounds of the formula I which contain acidic groups, for example carboxyl group, are, for example, alkali metal salts or alkaline earth metal salts such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions as well as acid addition salts with ammonia and with physiologically tolerable organic amines such as, for example, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. Compounds of the formula I which contain basic groups form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds of the formula I which contain a basic group as well as an acidic group, for example the guanidino group and a carboxyl group, can be present as zwitterions (betaines) which are likewise a subject of the present invention.
The physiologically tolerable anion Qxe2x88x92, which is contained in the compounds of the formula I when R4 is an alkyl residue that carries a positively charged ammonium group as substituent, is in particular a monovalent anion or an equivalent of a polyvalent anion of a nontoxic, physiologically utilizable or pharmaceutically utilizable inorganic or organic acid, for example the anion or an anion equivalent of one of the abovementioned acids suitable for the formation of acid addition salts. Qxe2x88x92 can thus be, for example, an anion (or an anion equivalent) like chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate or p-toluenesulfonate.
Salts of compounds of the formula I can be obtained by customary methods known to one skilled in the art, for example by combining a compound of the formula I with an inorganic or organic acid or base, respectively, in a solvent or dispersant, or from other salts by cation exchange or anion exchange. The present invention also includes all salts of the compounds of the formula I which, because of low physiologically tolerability, are not directly suitable for use in pharmaceuticals, but are suitable, for example, as intermediates for carrying out chemical modifications of the compounds of the formula I, or which are suitable as starting materials for the preparation of physiologically tolerable salts.
The present invention moreover includes all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I, for example esters, prodrugs and other physiologically tolerable derivatives, as well as active metabolites of the compounds of the formula I. The invention relates in particular to prodrugs of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions. Suitable prodrugs the compounds of the formula I, i.e. chemically modified derivatives of the compounds of the formula I which have properties that are improved in a desired manner, are known to those skilled in the art. More detailed information relating to prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; Design of. Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443; Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350. Suitable prodrugs for the compounds of the formula I are especially ester prodrugs of carboxylic acid groups, in particular of the COOH group which is present when R4 in the group COOR4 is hydrogen, and also acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups and in particular the guanidino group. In the acyl prodrugs or carbamate prodrugs once or more than once, for example once or twice, a hydrogen atom bonded to a nitrogen atom in a group like an amino group or a guanidino group is replaced with an acyl group or a carbamate group. Suitable acyl groups and carbamate groups for the acyl prodrugs and carbamate prodrugs are, for example, the groups R10xe2x80x94COxe2x80x94 and R11Oxe2x80x94COxe2x80x94, in which R10 is hydrogen, (C1-C18)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-, (C5-C14)-aryl, in which 1 to 5 carbon atoms can be replaced by heteroatoms such as N, O, S, or (C5-C14)-aryl-(C1-C8)-alkyl-, in which 1 to 5 carbon atoms in the aryl moiety can be replaced by heteroatoms such as N, O, S, and R11 has the meanings indicated for R10 with the exception of hydrogen.
The group A in the formula I can be, for example, the residue xe2x80x94(CH2)pxe2x80x94 in which p is 1, 2, 3, 4, 5, 6, 7, 8 or 9 and which can be unsubstituted or substituted as indicated above for the group A in general. Examples of a (C3-C7)-cycloalkylene residue representing the group A are 1,2-cyclopropylene or 1,2-cyclobutylene which can be unsubstituted or substituted as indicated above. If an alkylene or cycloalkylene residue representing A is substituted it is preferably substituted by one or two substituents. The group A preferably is a saturated or unsaturated bivalent (C1-C5)-alkylene residue, for example the residue xe2x80x94(CH2)pxe2x80x94 in which p is 1, 2, 3, 4 or 5, or is a bivalent (C3-C5)-cycloalkylene residue wherein the alkylene residue and the cycloalkylene residue each is unsubstituted or is substituted by one or two residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo. Particularly preferably A is a saturated or unsaturated bivalent (C1-C3)-alkylene residue, for example the residue xe2x80x94(CH2)pxe2x80x94 in which p is 1, 2, or 3, or is a bivalent (C3-C5)-cycloalkylene residue wherein the alkylene residue and the cycloalkylene residue each is unsubstituted or substituted by one or two residues from the series consisting of flourine, chlorine, bromine, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo. Especially preferably A is an unsubstituted (C1-C3)-alkylene group, for example a xe2x80x94CH2xe2x80x94 group-, a xe2x80x94CH2xe2x80x94CH2xe2x80x94 group, or a xe2x80x94CH2CH2CH2xe2x80x94 group.
Unless stated otherwise, aryl residues and heteroaryl residues present in the group B can be unsubstituted or substituted by one or more substituents as indicated above in detail for aryl residues and heteroaryl residues in general. If a (C1-C14)-alkyl group present in the group B is substituted by one or more halogen atoms it is preferably substituted by 1, 2, 3, 4, 5, 6 or 7 identical or different halogen atoms, particularly preferably by 1, 2, 3, 4 or 5 halogen atoms. The halogen atoms can be present in any desired positions. Preferred halogen atoms occurring as substituents in a (C1-C14)-alkyl group are fluorine and chlorine. The group B preferably is hydrogen, xe2x80x94NHxe2x80x94COxe2x80x94OR5, xe2x80x94NHxe2x80x94SO2(C1-C14)-alkyl wherein the alkyl group is unsubstituted or substituted by one or more halogen atoms, xe2x80x94NHxe2x80x94SO2(C6-C14)-aryl or xe2x80x94NHxe2x80x94SO2xe2x80x94(C5-C14)-heteroaryl. If D is (C6-C14)-aryl, (C5-C14)-heteroaryl or R5 the group B particularly preferably is hydrogen. If D is hydrogen the group B particularly preferably is a group different from hydrogen. If D is hydrogen the group B especially preferably is a group selected from the series consisting of xe2x80x94NHxe2x80x94COxe2x80x94OR5, xe2x80x94NHxe2x80x94SO2xe2x80x94(C1-C14)-alkyl wherein the alkyl group is unsubstituted or substituted by one or more halogen atoms, xe2x80x94NHxe2x80x94SO2xe2x80x94(C6-C14)-aryl and xe2x80x94NHxe2x80x94SO2xe2x80x94(C5-C14)-heteroaryl.
Unless stated otherwise, aryl residues and heteroaryl residues present in the group D can be unsubstituted or substituted by one or more substituents as indicated above in detail for aryl residues and heteroaryl residues in general. If B is hydrogen the group D preferably is (C6-C14)-aryl, (C5-C14)-heteroaryl or R5, particularly preferably (C6-C14)-aryl or (C5-C14)-heteroaryl. If B is a group different from hydrogen the group D preferably is hydrogen.
If alkyl residues representing R1 and/or R2 are substituted they are preferably independently of one another monosubstituted or disubstituted, in particular monosubstituted, by identical or different residues R3. If the residues R1 and R2 together are an alkylene residue which is substituted, the alkylene residue preferably is substituted by 1, 2, 3 or 4 identical or different substituents. An example of an alkylene residue representing R1 and R2 together is the residue xe2x80x94(CH2)pxe2x80x94, in which p is 2, 3, 4, 5, 6, 7, 8 or 9 and which can be unsubstituted or substituted as indicated above.
If the two residues R1 and R2 together represent a bivalent saturated or unsaturated (C2-C9)-alkylene residue these two residues together with the two nitrogen atoms to which they are bonded and the central carbon atom of the guanidino group to which these two nitrogen atoms are bonded, form a monocyclic 1,3-diazaheterocycle which is bonded to the nitrogen atom in the group Axe2x80x94COxe2x80x94NH via its 2-position. The 1,3-diazaheterocycle can be substituted as indicated above in the (C2-C9)-alkylene residue and/or on the guanidino nitrogen atom which forms part of the diazaheterocycle. Examples of residues of such 1,3-diazaheterocycles are the 2-imidazolyl residue, the 4,5-dihydro-2-imidazolyl residue, the 1,4,5,6-tetrahydro-2-pyrimidinyl residue or the 4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl residue. If a 5- to 7-membered ring is fused to a carbonxe2x80x94carbon bond in the (C2-C9)-alkylene residue, then the two residues R1 and R2 together with the two nitrogen atoms to which they are bonded and the central carbon atom of the guanidino group to which these two nitrogen atoms are bonded, form a bicyclic 1,3-diazaheterocycle which is bonded to the nitrogen atom in the group Axe2x80x94COxe2x80x94NH and which can be substituted as indicated. The fused (or condensed) 5- to 7-membered ring can be saturated or mono-unsaturated or di-unsaturated or aromatic. Thus, for example, a cyclopentane ring, a cyclohexane ring, a cyclohexene ring, a cyclohexadiene ring, a cycloheptane ring or a benzene ring can be condensed to a carbonxe2x80x94carbon bond in the (C2-C9)-alkylene residue. Examples of residues of such bicyclic heterocycles which can represent the group xe2x80x94C(xe2x95x90NR1)xe2x80x94NR2R6 and which thus can be bonded to the nitrogen atom in the group Axe2x80x94COxe2x80x94NH are the 1,3a,4,5,6,6a-hexahydro-1,3-diazapentalen-2-yl residue, the 1H-2-benzimidazolyl residue, the 3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl residue, the 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl residue, the 4,7-dihydro-1H-benzimidazol-2-yl residue or the 1H-imidazo[4,5-b]pyridin-2-yl residue. If a carbocyclic or heterocyclic ring fused to a carbonxe2x80x94carbon bond in an alkylene group representing R1 and R2 together is substituted it preferably is substituted by one or two identical or different residues R3.
The residues R1 and R2 preferably are hydrogen or together are a saturated or unsaturated, in particular a saturated, bivalent (C2-C5)-alkylene residue, in particular a (C2-C4)-alkylene residue, especially a (C2-C3)-alkylene residue, which is unsubstituted or is substituted by one or two identical or different residues, in particular by one residue, from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5- to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two residues R3, and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbonxe2x80x94carbon bond in the alkylene residue. The residues R1 and R2 particularly preferably are hydrogen or together are the residue xe2x80x94(CH2)pxe2x80x94, in which p is 2, 3, 4 or 5, preferably 2, 3 or 4, particularly preferably 2 or 3, and which is unsubstituted or is substituted by one to four, in particular one or two, identical or different residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5- to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two residues R3, and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbonxe2x80x94carbon bond in the residue xe2x80x94(CH2)pxe2x80x94. Especially preferably R1 and R2 both are hydrogen or R1 and R2 together are a 1,2-ethylene residue xe2x80x94CH2xe2x80x94CH2xe2x80x94 or a 1,3-propylene residue xe2x80x94CH2xe2x80x94CH2CH2xe2x80x94.
R3 preferably is (C1-C4)-alkyl or (C1-C4)-alkoxy.
R4 preferably is hydrogen or is unsubstituted or substituted (C1-C6)-alkyl, particularly preferably hydrogen or (C1-C6)-alkyl which is unsubstituted or substituted by a residue from the series consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94 and xe2x80x94NR7R7a, where R7 and R7a independently of one another are hydrogen or (C1-C4)-alkyl. R4 more particularly preferably is hydrogen or is unsubstituted or substituted (C1-C4)-alkyl, especially preferably hydrogen or (C1-C4)-alkyl which is unsubstituted or substituted by a residue from the series consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94 and xe2x80x94NR7R7a, where R7 and R7a independently of one another are hydrogen or (C1-C4)-alkyl, moreover preferably hydrogen or unsubstituted (C1-C4)-alkyl. If in an (C6-C14)-aryl-(C1-C6)-alkyl- residue or (C5-C14)-heteroaryl-(C1-C6)-alkyl- residue representing R5 the aryl residue or the heteroaryl residue is substituted it is preferably substituted by one, two or three identical or different substituents R3. A group R5 that is not bonded to a SO2 group preferably is (C1-C10)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- or a residue of the formula II 
in which the residues R1 can be identical or different and can be located in any desired positions of the phenyl residue, and wherein q is 0, 1 or 2, preferably 0 or 1, particularly preferably 0. Such a group R5 particularly preferably is (C1-C7)-alkyl, (C6-C12)-cycloalkyl, (C6-C12)-cycloalkyl-(C1-C4)-alkyl- or the residue of the formula II in which q is 0 or 1. Very particularly preferably such a group R5 is (C9-C12)-cycloalkyl-(C1-C3)-alkyl-, for example adamantylmethyl-, or the residue of the formula II in which q is 0 or 1. In this latter case the group R5 is an unsubstituted benzyl residue or a benzyl residue which is monosubstituted in the ortho-position, meta-position or para-position by a residue R3. A group R5 that is bonded to a SO2 group, i.e. a group R5 in the group xe2x80x94NHxe2x80x94SO2R5, preferably is (C1-C14)-alkyl wherein the alkyl group is unsubstituted or substituted by one or more halogen atoms, particularly preferably (C1-C10)-alkyl, more particularly preferably (C1-C7)-alkyl, wherein the alkyl groups are unsubstituted or substituted by one or more halogen atoms.
R6 preferably is hydrogen or (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94, particularly preferably hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94, especially preferably hydrogen.
Preferred compounds of the formula I are those compounds in which one or more of the residues defined in the general definition of the compounds of formula I have preferred meanings, all possible combinations of preferred meanings or of specific denotations expressly being a subject of the present invention. Preferred compounds are, for example, compounds of the formula I in which R1 and R2 both are hydrogen or R1 und R2 together are one of the bivalent residues 1,2-ethylene and 1,3-propylene, and R6 is hydrogen. Also with respect to all preferred compounds all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs are comprised by the present invention.
Particularly preferred compounds of the formula I are those compounds in which
A is a saturated or unsaturated bivalent (C1-C5)-alkylene residue or a bivalent (C3-C5)-cycloalkylene residue, wherein the alkylene residue and the cycloalkylene residue each is unsubstituted or is substituted by one or two residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo;
B is hydrogen, xe2x80x94NHxe2x80x94COxe2x80x94OR5, xe2x80x94NHxe2x80x94SO2xe2x80x94(C1-C14)-alkyl wherein the alkyl group is unsubstituted or substituted by one or more halogen atoms, xe2x80x94NHxe2x80x94SO2xe2x80x94(C6-C14)-aryl or xe2x80x94NHxe2x80x94SO2xe2x80x94(C5-C14)-heteroaryl;
D is hydrogen, (C6-C14)-aryl, (C5-C14)-heteroaryl or R5;
R1 and R2 are hydrogen or together are a saturated or unsaturated bivalent (C2-C5)-alkylene residue which is unsubstituted or is substituted by one or two residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5- to 7-membered saturated or unsaturated ring which is unsubstituted or substituted by R3 and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbonxe2x80x94carbon bond in the (C2-C5)-alkylene residue;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C5)-alkyl which is unsubstituted or is substituted by a residue from the series consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O) and xe2x80x94NR7R7a, where R7 and R7a independently of one another are hydrogen or (C1-C4)-alkyl;
R5 is (C1-C10)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- or a residue of the formula II 
xe2x80x83in which q is 0 or 1 and the residue R3 can be located in any desired position of the phenyl residue;
R6 is hydrogen or (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Very particularly preferred compounds of the formula I are those compounds in which
A is a saturated or unsaturated bivalent (C1-C3)-alkylene residue or a bivalent (C3-C5)-cycloalkylene residue, wherein the alkylene residue and the cycloalkylene residue each is unsubstituted or is substituted by one or two residues from the series consisting of flourine, chlorine, bromine, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo;
B is hydrogen, xe2x80x94NHxe2x80x94COxe2x80x94OR5, xe2x80x94NHxe2x80x94SO2xe2x80x94(C1-C14)-alkyl wherein the alkyl group is unsubstituted or substituted by one or more halogen atoms, xe2x80x94NHxe2x80x94SO2xe2x80x94(C6-C14)-aryl or xe2x80x94NHxe2x80x94SO2xe2x80x94(C5-C14)-heteroaryl;
D is hydrogen, (C6-C14)-aryl or (C5-C14)-heteroaryl;
R1 and R2 are hydrogen or together are a saturated or unsaturated bivalent (C2-C4)-alkylene residue which is unsubstituted or is substituted by one or two residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5- to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3 and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbonxe2x80x94carbon bond in the (C2-C4)-alkylene residue;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C6)-alkyl;
R5 is (C1-C7)-alkyl, (C6-C12)-cycloalkyl, (C6-C12)-cycloalkyl-(C1-C4)-alkyl- or a residue of the formula II 
xe2x80x83in which q is 0 or 1 and the residue R3 can be located in any desired position of the phenyl residue;
R6 is hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Especially preferred compounds of the formula I are those in which
A is a saturated or unsaturated bivalent (C1-C3)-alkylene residue or a bivalent (C3-C5)-cycloalkylene residue, wherein the alkylene residue and the cycloalkylene residue is unsubstituted;
B is hydrogen, xe2x80x94NHxe2x80x94COxe2x80x94OR5, xe2x80x94NHxe2x80x94SO2xe2x80x94(C1-C14)-alkyl wherein the alkyl group is unsubstituted or substituted by one or more halogen atoms, xe2x80x94NHxe2x80x94SO2xe2x80x94(C6-C14)-aryl or xe2x80x94NHxe2x80x94SO2(C5-C14)-heteroaryl;
D is hydrogen, (C6-C14)-aryl or (C5-C14)-heteroaryl;
R1 and R2 are hydrogen or together are a saturated or unsaturated bivalent (C2-C3)-alkylene residue which is unsubstituted, where a 5- to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3 and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbonxe2x80x94carbon bond in the (C2-C3)-alkylene residue;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C4)-alkyl;
R5 is (C1-C7)-alkyl, (C6-C12)-cycloalkyl, (C6-C12)-cycloalkyl-(C1-C4)-alkyl- or a residue of the formula II 
xe2x80x83in which q is 0 or 1 and the residue R3 can be located in any desired position of the phenyl residue;
R6 is hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
If the carbon atom to which the group B is bonded is chiral preferred compounds of the formula I are furthermore those in which the carbon atom to which the group B is bonded, has S configuration, in particular in compounds of the formula I in which D is hydrogen. Further, if the carbon atom to which the group D is bonded is chiral preferred compounds of the formula I are those in which the carbon atom to which the group D is bonded, has S configuration, in particular in compounds of the formula I in which B is hydrogen.
A specific group of compounds of the present invention is formed by the compounds of the formula I in which
A is a saturated or unsaturated bivalent (C1-C9)-alkylene residue or a bivalent (C3-C7)-cycloalkylene residue, wherein the alkylene residue and the cycloalkylene residue each is unsubstituted or is substituted by one or more residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C5-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)cycloalkyl-(C1-C6)-alkyl- and oxo;
B is hydrogen, xe2x80x94NHxe2x80x94COxe2x80x94OR5, xe2x80x94NHxe2x80x94SO2xe2x80x94R5, xe2x80x94NHxe2x80x94SO2xe2x80x94(C6-C14)-aryl, xe2x80x94NHxe2x80x94SO2xe2x80x94(C5-C14)-heteroaryl, xe2x80x94NHxe2x80x94COxe2x80x94R5, xe2x80x94NHxe2x80x94COxe2x80x94(C6-C14)-aryl, xe2x80x94NHxe2x80x94COxe2x80x94(C5-C14)-heteroaryl, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R5, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(C6-C14)-aryl, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(C5-C14)-heteroaryl, xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94R5, xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94(C6-C14)-aryl or xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94(C5-C14)-heteroaryl;
D is hydrogen, (C6-C14)-aryl, (C5-C14)-heteroaryl or R5;
R1 and R2 independently of one another are hydrogen or (C1-C6)-alkyl which is unsubstituted or substituted by one or more residues R3, or R1 and R2 together are a saturated or unsaturated bivalent (C2-C9)-alkylene residue which is unsubstituted or is substituted by one or more residues from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C6-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-Cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5- to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by one or more residues R3 and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbonxe2x80x94carbon bond in the (C2-C9)-alkylene residue;
R3 is (C1-C8)-alkyl, (C1-C8)-alkoxy, (C6-C14)-aryl, (C5-C14)-aryl-(C1-C4)-alkyl-, halogen, trifluoromethyl, hydroxyl, nitro or amino;
R4 is hydrogen, (C1-C6)-alkyl-COxe2x80x94Oxe2x80x94(C1-C4)-alkyl- or (C1-C6)-alkyl, which is unsubstituted or is substituted by a residue from the series consisting of hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94, xe2x80x94NR7R7a and xe2x80x94N+R7R7aR7bQxe2x88x92, where R7, R7a and R7b independently of one another are hydrogen, (C1-C6)-alkyl, (C5-C14)-aryl or (C5-C14)-aryl-(C1-C6)-alkyl- and Qxe2x88x92 is a physiologically tolerable anion, or R4 is one of the residues 
xe2x80x83in which the bonds via which the residues are bonded, are indicated by dashed lines;
R9 is (C1-C14)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C5)-alkyl-, (C6-C14)-aryl-(C1-C6)-alkyl- or (C5-C14)-heteroaryl-(C1-C6)-alkyl-, where the aryl residue and the heteroaryl residue is unsubstituted or is substituted by one or more residues R3;
R6 is hydrogen, (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94, hydroxyl, (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94Oxe2x80x94 or nitro; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
The present invention also relates to processes for the preparation of the compounds of the formula I. The compounds can generally be prepared, for example in the course of a convergent synthesis, by linkage of two or more fragments which can be derived retrosynthetically from the formula I. In the preparation of the compounds of the formula I it can generally be advantageous or necessary in the course of the synthesis to introduce functional groups which could lead to undesired reactions or side reactions in the respective synthesis step, in the form of precursor groups which are later converted into the desired functional groups, or to temporarily block functional groups by using a protective group strategy suitably adapted to the specific synthesis problem. Such strategies are well known to one skilled in the art (cf. Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991).
Thus the compounds of the formula I can be prepared, for example, by linking in a manner known per se a carboxylic acid or carboxylic acid derivative of the formula III 
in which R4, A, B and D are defined as indicated above for the formula I, or in which functional groups can also be present in the form of precursor groups which are later converted into the groups present in the compounds of the formula I, or functional groups can be present in protected form, and in which X is a nucleophilically substitutable leaving group examples of which are given below, with a guanidine or guanidine derivative of the formula IV 
in which R1, R2 and R5 are defined as indicated for the formula I, or in which functional groups can also be present in the form of precursor groups which are later converted into the groups present in the compounds of the formula I, or functional groups can be present in protected form. For example, in the compounds of the formula III the group R4 can, besides the denotations given for the formula I, also denote a carboxylic acid protecting group which after condensation of the compounds of the formulae III and IV is removed in order to obtain a compound of the formula I in which R4 is hydrogen. Similarly, for example, the condensation reaction can be performed with a compound of the formula III in which B denotes a group NH-PG wherein PG is an amino protecting group which is removed after the condensation reaction to yield a free amino group NH2 which is then converted into the desired target group, for example by sulfonylation or conversion into a carbamate group, amide group or urea group by standard procedures. Examples of precursor groups are nitro groups which can later be converted into amino groups, or cyano groups which can be converted into aminomethyl groups or carboxylic acid groups.
Beside the free guanidines of the formula IV also guanidinium salts can be employed in the reaction with the compounds of the formula III. In this case the free guanidines (can be prepared from their salts in situ or in a separate step by means of a base according to standard procedures.
The group COX in the formula III preferably is the carboxylic acid group COOH or an activated carboxylic acid derivative. X can be, for example, hydroxyl; halogen, in particular chlorine or bromine; alkoxy, preferably methoxy or ethoxy; aryloxy, for example phenoxy or pentafluorophenoxy; phenylthio; methylthio; 2-pyridylthio; or a residue of a nitrogen heterocycle bonded via a nitrogen atom, in particular a residue of an azole, such as, for example, 1-imidazolyl. Furthermore, an activated acid derivative can be a mixed anhydride, i.e. X can be, for example, ((C1-C4)-alkyl)-Oxe2x80x94COxe2x80x94Oxe2x80x94 or tolylsulfonyloxy.
If X is hydroxyl, i.e. if the guanidine of the formula IV is reacted with a carboxylic acid, then the carboxylic acid is expediently first activated. The activation can be carried out, for example, with dicyclohexylcarbodiimide (DCCl) or with O-((cyano(ethoxycarbonyl)methylen)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU; Kxc3x6nig et al., Proc. 21st Europ. Peptide Symp. 1990 (Eds. Giralt, Andreu), Escom, Leiden 1991, p. 143) or with other activating reagents customary in peptide chemistry.
The reaction of an activated carboxylic acid derivative of the formula III with the guanidine (derivative) of the formula IV is preferably carried out in a manner known per se in a protic or aprotic polar, but inert, organic solvent. In this case, methanol, isopropanol, tert-butanol, dimethylformamide or tetrahydrofuran at temperatures from 0xc2x0 C. up to the boiling point of these solvents have proven suitable, for example, in the reaction of a methyl ester (X=methoxy) or of an ethyl ester (X=ethoxy) with a guanidine (derivative). The reactions of compounds of the type COX with salt-free guanidines are advantageously carried out in aprotic inert solvents such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if appropriate with addition of a base such as, for example, potassium tert-butoxide or sodium methoxide. However, water can also be used as a solvent in the reaction of compounds of the formula III with guanidines, for example when using a base such as sodium hydroxide. If X is chlorine, the reaction is advantageously carried out with addition of an acid scavenger, for example with addition of an added base or in the presence of excess guanidine (derivative), for binding the resulting hydrohalic acid. The reaction mixture is worked up and, if desired, the reaction product is then purified by the customary processes familiar to one skilled in the art.
Protective groups optionally still present in the products obtained from the starting compounds of the formulae III and IV are then removed by standard processes. For example, tert-butyl ester groups can be converted into the carboxylic acid groups by treatment with trifluoroacetic acid, benzyl groups can be removed by hydrogenation, or fluorenylmethoxycarbonyl groups can be removed by secondary amines. If desired, further reactions, for example acylation reactions, can be carried out by standard processes, as well as a conversion into a physiologically tolerable salt or into a prodrug can be carried out by known processes.
The starting components of the formulae III and IV, which are linked to give the acylguanidine derivatives of the formula I, are commercially available or can be prepared by or analogously to processes described in the literature. Synthetic ways for preparing starting components of the formula III are exemplarily illustrated in scheme 1. The present invention, however, is not restricted to the depicted syntheses or starting components. It does not cause any problems to one 
skilled in the art to carry out the modifications of the syntheses shown which are necessary for the preparation of other compounds according to the invention. The synthesis of a compound of the formula III may, for example, start from a bromothiophene carboxylic acid or a derivative thereof of the formula V in which R21 is, for example, hydrogen, (C1-C4)-alkyl, benzyl or a carboxylic acid protective group. A compound of the formula V can be coupled in the presence of a transition metal catalyst like, for example, a palladium complex with an xcex1,xcex2-unsaturated carboxylic acid derivative of the formula VI in which R22 can be, for example, (C1-C4)-alkyl. R31 and R32 in formula VI, as well as in formula VII, can be hydrogen or carbon substituents that can be present in an alkylene group representing the group A in the compounds of formula I, or R31 and R32 together with the two carbon atoms to which they are bonded may form a cycloalkene ring, where functional groups present in R31 and R32 may also be present in protected form or in the form of precursor groups. Such a coupling reaction yielding a compound of formula VII, just as any other reaction mentioned in this section on the synthesis of compounds of the formula III, can be performed under conditions comprehensively described in the literature and/or in the experimental section. The resulting compound of the formula VII may already be a compound which without further modifications is reacted with an amino acid derivative of the formula XIII (see below) to give a compound of the formula XIV. However, before being reacted with a compound of the formula XII a compound of the formula VII may also first be modified in one or more reaction steps in the groups COOR21 and/or COOR22 and/or in the CR31xe2x95x90CR32 moiety. For example, an ester group may be cleaved to give a carboxylic acid group and/or an activated carboxylic acid derivative may be prepared. The double bond in the CR31xe2x95x90CR32 moiety may, for example, be modified by catalytic hydrogenation to give a single bond, or by cyclopropanation with a carbene transferring reagent like an diazoalkane, a sulfur ylide or methylene iodide to give a cyclopropane derivative. After such modifications a compound of the formula XII is obtained in which the group X1 is a nucleophilically substitutable leaving group. All the above statements with respect to the group X in the compounds of the formula III also apply to the group X1 in the compounds of formula XII. The group R25 is, for example, hydrogen, (C1-C4)-alkyl, benzyl or a carboxylic acid protective group. The group A1 is defined as the group A in the compounds of the formula I or can also be a precursor group of the group A which can be transformed into the desired group A, or can also contain functional groups in protected form.
In a further synthetic route to compounds of the formula III a protected thiophene aldehyde of the formula VIII is employed as starting material. In formula VIII the groups R33 and R34 are, for example, alkoxy groups or dialkylamino groups, or the groups R33 and R4 together with the CH group to which they are bonded form a heteroyclic ring like, for example, a 1,3-dioxolane ring, a perhydro-1,3-dioxane ring, an N,Nxe2x80x2-dialkylimidazolidine ring, an N-alkyl-1,3-oxazolidine ring or an N-alkylperhydro-1,3-oxazine ring which all may carry further substituents like alkyl groups, and wherein alkyl preferably denotes (C1-C4)-alkyl. After metallation with, for example, an organolithium compound like butyl lithium a compound of the formula VIII is reacted with a reagent introducing a carboxylic acid function, for example with a dicarbonic acid ester of the formula O(COOR23)2 or a chloroformic acid ester of the formula in ClCOOR3 wherein R23 is, for example, (C1-C4)-alkyl or benzyl. In the primary reaction product the protected aldehyde group is deprotected to give a formylthiophene carboxylic acid derivative of formula IX in which, as in formula XI, the group R23 is for example (C1-C4)-alkyl or benzyl. The aldehyde function in the compound of formula IX is then converted into an olefine under standard olefination conditions by reacting it with a suitable compound of the formula X. In addition, aldehydes of formula IX are also suitable starting materials for the preparation of compounds of the present invention in which A in the formula I is C1-alkylene, i.e. a methylene group. For the preparation of these latter compounds the aldehyde function may, for example, be reduced to a hydroxymethyl group which after activation by mesylation or tosylation can be converted into a CH2xe2x80x94CN group wherein the CN group can then be converted into a carboxylic acid or an ester thereof.
Examples of compounds of the formula X are malonic acid derivatives or phosphorus compounds like phosphonic acid esters or phosphonium salts. In the case of malonic acid derivatives the group R35 in the formula X is a carboxylic acid group (or a salt thereof), R36 is hydrogen, A0 is a direct bond, and R24 is, for example, (C1-C4)-alkyl. In the case of phosphorus compounds the group R35 in the formula X may be a positively charged phosphonium salt group having a negative counterion, for example a triphenylphosphonium group with chloride, bromide or iodide as counterion, or the group R35 may be a phosphonic acid ester group, for example a diethyl phosphonate group of the formula (C2H5O)2P(O)xe2x80x94. In phosphorus compounds of the formula X the group R36 is hydrogen or a carbon substituent that can be present in an alkylene group representing the group A in the compounds of the formula I, and the group R24 is, for example, (C1-C4)-alkyl or benzyl. The group A0 in phosphorus compounds of the formula X is a direct bond or a saturated or unsaturated bivalent (C1-C7)-alkylene residue. The definitions given for the compounds of the formulae IX and X also apply to the compounds of the formula XI.
Condensations of the compounds of formulae IX and X can be carried out under standard conditions. If the compound of formula X is a malonic acid ester salt, the components may be reacted, for example, in the presence of pyridine and piperidine. If the compound of the formula X is a phosphonium salt or a phosphonic acid ester, according to the customary procedure applied in Wittig reactions or Wittig Horner reactions, it usually is first deprotonated with a suitable base like, for example, sodium hydride, lithium diisopropylamide, potassium tert-butoxide or another alkali metal alcoholate to give a phosphorane or a metal salt of the phosphonic acid ester, respectively, and is then reacted with the aldehyde of formula IX. The resulting compound of formula XI, like the compounds of formula VII, may already be a compound which without further modifications is reacted with an amino acid derivative of the formula XIII to give a compound of the formula XIV. However, before being reacted with a compound of the formula XIII a compound of the formula XI may also first be modified in one or more reaction steps in the groups COOR23 and/or COOR24 and/or in the CHxe2x95x90CR36 moiety and/or in the group A0, for example by cleaving ester groups and/or preparing an activated carboxylic acid derivative and/or modifying double bonds by catalytic hydrogenation or by cyclopropanation. After such modifications a compound of the formula XII is obtained in which the residues have the meanings already indicated above.
In the compounds of formula XIII, as well as in the compounds of formula XIV, the residues R26, B1 and D1 have the meanings of the residues R4, B and D, respectively, in the compounds of formula I, but functional groups within them can also be present in the form of precursor groups or can be present in protected form. If in the desired target compound of formula I the group B denotes hydrogen, the corresponding starting compound of the formula XIII is a 3-aminopropionic acid derivative. If in the target compound the group B is a substituted amino group, the corresponding starting compound of the formula XIII is a 2,3-diaminopropionic acid derivative. If X1 in the formula XII is hydroxyl the condensation of the NH2 group in the propionic acid derivative of formula XIII with the COX1 group in the compound of formula XII can be carried similarly as described above for the condensation of the compounds of formulae III and IV, for example in the presence of TOTU or another customary activating agent for carboxylic acids, and the above statements then correspondingly also apply to the present reaction. The resulting condensation product of the formula XIV may already be a compound which without further modifications is reacted with a guanidine (derivative) of the formula IV. In such a case the compound of the formula XIV also is a compound of the formula III. However, before being reacted with a compound of the formula IV, a compound of the formula XIV may also first be modified in one or more reaction steps in the groups COOR25 and/or COOR26 and/or in further groups like the groups A1 or B1. For example, an ester group representing the group COOR25 may be cleaved to give a carboxylic acid group, and/or an activated carboxylic acid derivative may be prepared. A double bond present in the group A1 may, for example, be modified by catalytic hydrogenation to give a single bond, or by cyclopropanation as outlined above. After such modifications a compound of the formula III is obtained.
Thus, if in a compound of formula XIV obtained from the syntheses described above the group COOR25 is an activated carboxylic acid derivative, the compound of formula XIV can be reacted directly with a compound of formula IV. If in a compound of formula XIV the group COOR25 is an ester group and it is not intended to react this compound directly with a compound of formula IV, the ester group can also first be cleaved under standard conditions to give the corresponding carboxylic acid which is then reacted with a guanidine of formula IV after in situ activation, for example with TOTU or DCCl, or after conversion into an activated carboxylic acid derivative. If, as activated acid derivative, it is intended to prepare, for example, the carboxylic acid chloride (formula III, X=Cl), this can be carried out by using, for example, thionyl chloride. If it is intended to prepare, for example, the methyl ester (X=methoxy) from the carboxylic acid, this can be carried out by treating with gaseous hydrogen chloride in methanol. Other activated acid derivatives can be prepared in a manner known per se from the carboxylic acid chlorides or directly from the carboxylic acids on which they are based (X=OH), for example the imidazolides (X=1-imidazolyl) by treating the acids with carbonyldiimidazole (cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)), or for example the mixed anhydrides by reaction with chloroformic acid esters such as ethyl chloroformate or with tosyl chloride in the presence of an amine such as triethylamine in an inert solvent. A number of suitable methods for the preparation of activated carboxylic acid derivatives are indicated with details of source literature in J. March, Advanced Organic Chemistry, Third Edition, John Wiley and Sons, 1985, p. 350.
The compounds of the formula I are valuable pharmaceutical active compounds which are suitable, for example, for the therapy and prophylaxis of bone disorders, tumor diseases or cardiovascular disorders. The compounds of the formula I and their physiologically tolerable salts and their prodrugs can be administered to animals, preferably to mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be administered on their own, in mixtures with one another or in the form of pharmaceutical preparations (or pharmaceutical compositions) which permit enteral or parenteral administration and which, as active ingredient, contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs in addition to customary pharmaceutically acceptable carriers and/or additives.
The present invention therefore also relates to the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for use as pharmaceuticals, to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the production of pharmaceuticals for the therapy and prophylaxis of the diseases mentioned above or below, for example for the therapy and prophylaxis of bone disorders, and also to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs in the therapy and prophylaxis of these diseases. The present invention furthermore relates to pharmaceutical preparations which contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs in addition to a customary pharmaceutically acceptable carrier.
The pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or transdermally, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
The pharmaceutical preparations according to the invention are prepared in a manner known per se, pharmaceutically inert inorganic and/or organic carriers or excipients being used in addition to the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.
In addition to the active ingredients and carriers, the pharmaceutical preparations can additionally contain additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs. Furthermore, in addition to at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs, they can also contain one or more other therapeutically or prophylactically active ingredients.
The pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs. The amount of active ingredient of the formula I and/or its physiologically tolerable salts and/or its prodrugs in a pharmaceutical preparation normally is 0.2 to 1000 mg, preferably 1 to 200 mg.
The compounds of the formula I are antagonists of the vitronectin receptor and have, for example, the ability to inhibit the binding of osteoclasts to the bone surface and thereby inhibit bone resorption by osteoclasts. The action of the compounds of the formula I can be demonstrated, for example, in an assay in which the inhibition of the binding of vitronectin to cells which contain the vitronectin receptor is determined. Details of such an assay are given below. As vitronectin receptor antagonists, the compounds of the formula I and their physiologically tolerable salts and their prodrugs are generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cell cell interaction processes or cell matrix interaction processes, or which can be influenced by an inhibition of interactions of this type, or for the prevention, alleviation or cure of which an inhibition of interactions of this type is desired. As explained at the beginning, such interactions play a part, for example, in bone resorption, in angiogenesis or in the proliferation of cells of the vascular smooth musculature. The compounds of the formula I and their physiologically tolerable salts and their prodrugs are therefore suitable, for example, for the alleviation or cure of diseases which are caused at least partially by an undesired extent of bone resorption, angiogenesis or proliferation of cells of the vascular smooth musculature.
Bone diseases for whose treatment and prevention the compounds of the formula I according to the invention can be employed are especially osteoporosis, hypercalcemia, osteopenia, for example caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget""s disease. In addition, the compounds of the formula I can be used for the allevation, avoidance or therapy of bone disorders which are caused by a glucocorticoid, steroid or corticosteroid therapy or by a lack of sex hormone(s). All these disorders are characterized by bone loss which is based on the inequilibrium between bone formation and bone destruction and which can favorably be influenced by the inhibition of bone resorption by osteoclasts.
The compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also favorably be used as inhibitor of bone resorption, for example in the therapy or prophylaxis of osteoporosis, in combination with conventional osteoporosis treatments, for example in combination with agents like bisphosphonates, estrogens, estrogen/progesterone, estrogen agonists/antagonists, calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride. Administration of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs and of other active ingredients effective in the treatment or prophylaxis of osteoporosis like those listed before can take place simultaneously or sequentially, in any order, and jointly or separately. For use in such a combination treatment or prophylaxis the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs and one or more other active ingredients like those listed before can together be present in a single pharmaceutical preparation, for example tablets, capsules or granules, or can be present in two or more separate pharmaceutical preparations which can be contained in a single package or in two or more separate packages. The use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs in such a combination therapy or prophylaxis and their use in the production of pharmaceuticals for such a combination therapy or prophylaxis are also subjects of the present invention. The invention furthermore relates to pharmaceutical preparations which comprise efficacious amounts of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs together with at least one other active ingredient effective in the treatment or prophylaxis of osteoporosis or in the inhibition of bone resorption like those listed before, together with a customary pharmaceutically acceptable carrier. The above explanations on pharmaceutical preparations correspondingly apply to such pharmaceutical combination preparations.
In addition to the use as inhibitors of bone resorption by osteoclasts, the compounds of the formula I and their physiologically tolerable salts and their prodrugs can be used, for example, as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the therapy or prophylaxis of cardiovascular disorders such as arteriosclerosis or restenosis, or for the therapy or prophylaxis of nephropathies or retinopathies such as, for example, diabetic retinopathy. As inhibitors of tumor growth or tumor metastasis the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also favorably be used in combination with conventional cancer therapy. Examples of conventional cancer therapy are given in Bertino (Editor), Encyclopedia of Cancer, Academic Press, 1997 which is incorporated herein by reference. All the above statements relating to the use of the compounds of formula I in combination with conventional osteoporosis therapy like, for example, possible modes of administration and pharmaceutical combination preparations, correspondingly apply to the use of the compounds of formula I in combination with conventional cancer therapy.
When using the compounds of the formula I, the dose can vary within wide limits. As is known to those skilled in the art, the dose is to be suited to the individual conditions in each individual case. It depends, for example, on the compound employed, on the nature and severity of the disease to be treated and on whether an acute or chronic condition is treated or whether prophylaxis is carried out. In the case of oral administration, for achieving effective results in an adult weighing about 75 kg the daily dose generally is about 0.01 to 100 mg/kg, preferably about 0.1 to 50 mg/kg, in particular about 0.1 to 10 mg/kg (in each case in mg per kg of body weight). Also in the case of intravenous administration the daily dose generally is about 0.01 to 100 mg/kg, preferably about 0.05 to 10 mg/kg (in each case in mg per kg of body weight). The daily dose can be divided, in particular in the case of administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upwards or downwards from the daily dose indicated.
Beside their use as active ingredients in pharmaceutical preparations, the compounds of the formula I can also be used as vehicles or carriers of other active ingredients in order to transport the other active ingredient specifically to the site of action (=drug targeting; see, for example, Targeted Drug Delivery, R. C. Juliano, Handbook of Experimental Pharmacology, Vol. 100, Ed. Born, G. V. R. et al., Springer Verlag). The active ingredients to be transported are in particular those which can be used for the treatment of the abovementioned diseases.
The compounds of the formula I and their salts can furthermore be employed for diagnostic purposes, for example in in vitro diagnoses, and as auxiliaries in biochemical investigations when blocking of the vitronectin receptor or influencing of cell cell or cell matrix interactions is desired for diagnostic or research purposes. They can furthermore be used as intermediates for the preparation of other compounds, in particular of other pharmaceutical active compounds, which are obtainable from the compounds of the formula I, for example by chemical modification or introduction of residues or functional groups.